The overall objective of the proposed work is to study the effect of renal failure on the hepatic metabolism of drugs. Our initial investigations will aim at exploring the mechanisms responsible for the pronounced inhibition of the presystemic or "first pass" metabolism of propranolol as previously reported in chronic renal failure patients. The metabolism of propranolol will be studied in various uremic animal models. Appropriate experiments with isolated perfused liver preparation will be performed to determine if the inhibition of propranolol metabolism in uremia is due to the accumulation of "endogenous inhibitors" in uremic blood or rather to a pathological alteration in the microsomal enzyme systems. If the presence of "endogenous inhibitors" is indicated, in vitro experiments with hepatic microsomes or isolated hepatocytes will be carried out to characterize the kinetic failure nature of this inhibition. On the other hand, if alteration of microsomal enzyme system is indicated, microsomal protein and cytochrome P-450 contents of uremic and normal rat liver will be compared. Finally, the possibility that the accumulation of propranolol metabolites in uremic blood can inhibit the metabolism of the parent drug will also be investigated.